Process for preparation of 2-aminothiazolecarboxamide derivatives

ABSTRACT

A process for preparing a compound represented by formula (I), wherein R 1  represents straight-chain or branched C 1-5  alkyl, C 1-5  haloalkyl, or C 3-6  cycloalkyl, and R 2  represents C 1-3  alkyl or C 1-3  haloalkyl.

TECHNICAL FIELD

[0001] The present invention relates to a process for preparation of a2-aminothiazolecarboxamide derivative represented by the followingformula (I)

[0002] wherein R¹ represents straight-chain or branched C₁₋₅ alkyl, C₁₋₅haloalkyl, or C₃₋₆ cycloalkyl, and R² represents C₁₋₃ alkyl or C₁₋₃haloalkyl.

BACKGROUND ART

[0003] The compounds of formula (I) are used as microbicides fortreating plant diseases caused by Pythiaceae or Peronosporaceae. Thecompounds of formula (I) were already disclosed in Korean PatentLaid-open Publication No. 94-19960 and the corresponding foreignapplications, for example, U.S. patent application Ser. No 08/287,917,JP Patent Application No. 192529 and EP Patent Application No 94112652.6which were filed by the present applicant.

[0004] Further, a process for preparation of 2-aminothiazolecarboxamidederivatives including the compounds of formula (I) using 2-aminothiazolecarboxylic acid as an intermediate was described in Korean PatentLaid-open Publication No 97-24120. However, this process has thedisadvantage that it is not economic when applied to industrialproduction due to the many steps for obtaining the intermediate and thelow yield.

[0005] Accordingly, the present inventors have studied to improve theprior process by solving the above mentioned problems, and as a result,have brought the present invention to completion.

DISCLOSURE OF THE INVENTION

[0006] The present invention relates to a process for preparation of a2-arninothiazolecarboxamide derivative represented by the above formula(I) characterized in that an iminothiourea compound represented by thefollowing formula (II):

[0007] wherein R¹ and R² are defined as previously described, and R³represents phenyl which may be optionally mono- to penta-substitutedindependently by chloro, methoxy, ethoxy, phenoxy or nitro, is reactedwith a thiopheneacetamide compound represented by the following formula(III):

[0008] wherein Y represents a leaving group such as chloride, bromide,etc.

BEST MODE FOR CARRYING OUT THE INVENTION

[0009] The compound of formula (I) can be prepared by reacting thecompound of formula (II) with the compound of formula (III) in a solventand in the presence of a base as depicted in the following ReactionScheme 1.

[0010] wherein R¹, R², R³ and Y are defined as previously described.

[0011] Examples of the base used in the above reaction include anorganic base such as triethylamine, tributylamine,diisopropylethylamine, N,N-dimethylaniline, pyridine,4-dimethylaminopyridine, etc., and an inorganic base such as sodiumhydroxide, potassium hydroxide, potassium carbonate, sodiumhydrogencarbonate, potassium hydrogencarbonate, sodium hydride,potassium hydride, etc. The organic base is preferred, and the alkylamine such as triethylamine, tributylamine, diisopropylethylamine, etcis more preferred. The base can be used in an amount of 1 to 5equivalents, preferably in an amount of 1 to 2 equivalents.

[0012] The above reaction can be carried out at the temperature between20 and 120° C., preferably between 40 and 80° C., and the reaction timeis suitably about 8 to 12 hours.

[0013] The solvent includes an alcohol such as methanol, ethanol,isopropyl alcohol, etc., an aromatic hydrocarbon such as benzene,toluene, xylene, etc, an ether such as diethylether, dioxane,1,2-dimethoxyethane, tetrahydrofuran, etc, a ketone such as acetone,methylethyl ketone, cyclohexanone, etc.; a nitrile such as acetonitrile,propionitrile, etc.; a halogenated hydrocarbon such as dichloromethane,1,2-dichloroethane, chloroform, etc, an ester such as methyl acetate,ethyl acetate, etc.; and a polar solvent such as N,N-diethylformamide,N,N-dimethylacetamide, dimethyl sulfoxide, etc., and the alcohol ispreferred

[0014] The compound of formula (II) used as a starting material in theReaction Scheme (I) is novel and can be prepared in accordance with thefollowing Reaction Scheme (II):

[0015] wherein R¹, R² and R³ are defined as previously described.

[0016] That is, the compound of formula (II) can be prepared by aprocess characterized in that

[0017] in Step 1, an amide compound represented by the following formula(IV)

[0018] wherein R² and R³ are defined as previously described, is reactedwith a halogenating agent in a solvent in the presence of a base toproduce an imidoylchloride compound represented by the following formula(V):

[0019] wherein R² and R³ are defined as previously described,

[0020] in Step 2, the resulting imidoylchloride compound of formula (V)is reacted with an isothiocyanide compound represented by the followingformula (VII):

MSCN   (VII)

[0021] wherein M represents an alkali metal such as sodium, potassium,etc., or NH₄, by which the chloride group is replaced with theisothiocyanide group to produce an imidoylisothiocyanate compoundrepresented by the following formula (VI).

[0022] wherein R² and R³ are defined as previously described,

[0023] in Step 3, the resulting imidoylisothiocyanate compound offormula (VI) is reacted with a primary amine compound represented by thefollowing formula (VIII)

R¹—NH₂   (VIII)

[0024] wherein R¹ is defined as previously described, in the presence ofa base

[0025] In Step 1 for preparing the imidoylchloride compound of formula(V), thionyl chloride (SOCl₂), phosgene (COCl₂), phosphorus oxychloride(POCl₃), etc. can be used as the halogenating agent. The halogenatingagent is suitably used in an amount of 1 to 4 equivalents. This reactionis carried out at the temperature between −20° C. and 80° C., preferablybetween −10° C. and 20° C. The reaction time is suitably about 2 to 5hours. As the base, an organic base such as pyridine,4-dimethylaminopyridine, triethylamine, N,N-dimethyl aniline,tributylamine, etc. can be used. A mild base such as pyridine ispreferred. The base is suitably used in an amount of 1 to 4 equivalents.

[0026] As the solvent, an aromatic hydrocarbon such as benzene, toluene,xylene, etc.; a halogenated hydrocarbon such as dichloromethane,1,2-dichloroethane, chloroform, etc.; an ether such as diethylether,dioxane, 1,2-dimethoxyethane, tetrahydrofuran, etc.; a ketone such asacetone, methylethyl ketone, cyclohexanone, etc.; a nitrile such asacetonitrile, propionitrile, etc.; an ester such as methyl acetate,ethyl acetate, etc., or a polar solvent such as N,N-dimethylformamide,N,N-dimethylacetamide, dimethyl sulfoxide, etc., preferably ahalogenated hydrocarbon such as dichloroethane, chloroform, etc. can beused. In addition, N,N-dimethylformamide can be used as a catalyst.

[0027] In Step 2, the imidoylisothiocyanate compound of formula (VI) isprepared by reacting the imidoylchloride compound of formula (V)prepared in step 1 with the isothiocyanide compound of formula (VII).The isothiocyanide compound of formula (VII) is suitably used in anamount of 1 to 2 equivalent. The reaction temperature can be between−20° C. and 50°C., preferably between 0° C. and 20° C., and the reactiontime ranges suitably from 2 to 5 hours.

[0028] In step 3, the iminothiourea compound of formula (II) is preparedfrom the imidoylisothiocyanate compound of formula (VI). In this step,the carbon atom of isothiocyanate is attacked by the amine compound offormula (VIII) in the presence of a base, by which the thioureaderivative of formula (II) is produced. The amine compound of formula(VIII) can be used in an amount of 1 to 4 equivalents, preferably 2 to 3equivalents. This reaction can be carried out at the temperature between−20° C. and 80° C., preferably between 0° C., and 30° C. The reactiontime is suitably from 2 to 4 hours.

[0029] The above processes according to the present invention will bemore specifically explained through the following examples. As typicalexamples of the compounds of formula (II) according to the presentinvention, those described in the following table (I) can be mentioned.TABLE 1 COM. NO. R¹ R² R³ 1 ethyl methyl phenyl 2 ethyl ethyl phenyl 3ethyl ethyl 2,6-dichlorophenyl 4 ethyl ethyl 4-methoxyphenyl 5 ethylethyl 4-phenoxyphenyl 6 ethyl ethyl 4-nitrophenyl 7 n-butyl methylphenyl 8 n-butyl ethyl phenyl 9 isopropyl ethyl phenyl 10 isopropylmethyl phenyl

[0030] The compound of formula (III) used as a starting material in theReaction Scheme (I) is also a novel compound, and can be prepared inaccordance with the following Reaction Scheme (III).

[0031] wherein Y is defined as previously described.

[0032] That is, the compound of formula (III) can be prepared by aprocess characterized in that

[0033] in Step 1, an aldehyde compound represented by the followingformula (IX)

[0034] is converted into an aminonitrile compound represented by thefollowing formula (X)

[0035] through the known Strecker Synthesis,

[0036] in Step 2, the resulting aminonitrile compound of formula (X) isreacted with a compound represented by the following formula (XI).

[0037] wherein Y is defined as previously described, in the presence ofa base.

[0038] In Step 1 of the above reaction, the aldehyde compound of formula(IX) can be readily converted into the aminonitrile compound of formula(X) through the known Strecker Synthesis as stated above.

[0039] In Step 2, the thiopheneacetamide compound of formula (III) canbe prepared by reacting the aminonitrile compound of formula (X) with 1to 3 equivalents, preferably 1 to 1.5 equivalents of chloroacetylchloride or bromoacetyl bromide of formula (XI) in the presence of abase. This reaction can be carried out at the temperature between −20°C. and 80° C., preferably between 0° C. and 20° C. The reaction time issuitably from 30 minutes to 2 hours.

[0040] As the base, an organic base such as pyridine,4-dimethylaminopyridine, triethylamine, N,N-dimethyl aniline,tributylamine, diisopropylethylamine, etc., preferably pyridine or4-dimethylamino pyridine can be used. The base can be suitably used inan amount of 1 to 3 equivalents.

[0041] As the solvent, a halogenated hydrocarbon such asdichloromethane, 1,2-dichloroethane, chloroform, etc.; an aromatichydrocarbon such as bezene, toluene, xylene, etc.; an ether such asdiethylether, dioxane, 1,2-dimethoxy ethane, tetrahydrofuran, etc.; aketone such as acetone, methylethyl ketone, cyclohexanone, etc.; anitrile such as acetonitrile, propionitrile, etc.; an ester such asmethyl acetate, ethyl acetate, etc., or a polar solvent such asN,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, etc.,preferably a halogenated hydrocarbon or an aromatic hydrocarbon can beused.

[0042] The present invention is more specifically explained by thefollowing preparation and examples. However, it should be understoodthat the present invention is not limited to these examples in anymanner.

Preparation 1: Synthesis of N-phenyl-propionamide

[0043] Into a reaction vessel were placed aniline (279.4 g, 3.0 mol) anddichloromethane (2400 g), the reaction vessel was cooled to 0° C., andsodium hydroxide (132.0 g, 3.3 mol) dissolved in water (660 g) wasslowly added dropwise thereto.

[0044] It was confirmed that the temperature of the reaction vessel was0° C. and then propionyl chloride (291.5 g, 3.2 mol) was added dropwisethereto for 2 hours. And then the mixture was stirred at roomtemperature (20° C.) for 2 hours, and the reaction was completed. Afterthe reaction was completed, the layers were separated, anddichloromethane was removed by distillation under the reduced pressureto produce a brown solid. The solid was recrystallized from toluene togive the title compound (434.7 g, 2.9 mol) in a yield of 97%.

[0045]¹H NMR (CDCl₃): δ 7.75(1H, s, br), 7.52(2H, d), 7.29(2H, d),7.08(1H, t), 2.37(2H, q), 1.22(3H, t)

EXAMPLE 1: Synthesis of N-ethyl-N′-(1-phenyliminopropyl)-thiourea

[0046] N-phenylpropionamide (149.2 g, 1.0 mol) and pyridine (261.0 g,3.3 mol) were dissolved in dichloromethane (300 g), and the mixture wascooled to 0° C. Phosphorus oxychloride (168.7 g, 1.1 mol) was addeddropwise thereto for 2 hours, and then the mixture was stirred at roomtemperature (20° C.) for 2 hours to produceN-phenylpropionimidoylchloride

[0047] Subsequently, the reactant was slowly added dropwise to thereaction vessel containing the mixture of potassium isothiocyanide(145.8 g, 1.5 mol) and sodium carbonate (318.0 g, 3.0 mol) in acetone(1,000 ml) at the temperature of 10° C. or less for 2 hours and then themixture was stirred for 1 hour to produce N-phenylpropionimidoylisothiocyanate. Ethylamine (128.8 g, 2.0 mol) was added dropwise theretomaintaining the temperature of 10° C. or less for 2 hours, and then themixture was stirred for 1 hour.

[0048] After the reaction was completed, the solvent was removed bydistillation under reduced pressure. And the product was extracted bytoluene and washed with sodium hydroxide solution And then the toluenewas removed by distillation under reduced pressure, and the residue wasrecrystallized from isopropyl alcohol to give the title compound (157.2g, 0.7 mol) in a yield of 67%.

[0049]¹H NMR (CDCl₃): δ 11.84(1H, s, br), 8.18(1H, s, br), 7.32(2H, m),7.12(1H, t), 6.79(2H, d), 3.69(2H, m), 2.23(2H, q), 1.26(3H, t),1.15(3H, t)

EXAMPLE 2: Synthesis of N-(1-(2,6-dichlorophenyl)iminopropyl))-N′-ethylthiourea

[0050] N-(2,6-dichlorobenzene)propionamide (21.8 g, 0.1 mol) andpyridine (27.7 g, 0.35 mol) were dissolved in dichloromethane (30 g),and the mixture was cooled to 0° C. Phosphorus oxychloride (16.9 g, 0.11mol) was added dropwise thereto for 2 hours, and then the mixture wasstirred at room temperature (20° C.) for 2 hours to produceN-(2,6-dichloro benzene)propionimidoylchloride.

[0051] Subsequently, the reactant was slowly added dropwise to thereaction vessel containing the mixture of potassium isothiocyanide (14.6g, 0.15 mol) and sodium carbonate (31.8 g, 0.3 mol) in acetone (100 ml)at the temperature of 10° C. or less for 2 hours, and then the mixturewas stirred for 1 hour to produce N-(2,6-dichlorobenzene)propionimidoylisothiocyanate. Ethylamine (12.9 g, 0.2 mol) was added dropwise theretomaintaining the temperature of 10° C. or less for 2 hours, and then themixture was stirred for 1 hour.

[0052] After the reaction was completed, the title compound (21.9 g, 72mmol) was obtained in a yield of 72% according to the same procedure asExample 1.

[0053]¹NMR (CDCl₃) δ 11.69(1H, s, br), 8.65(1H, s, br), 7.43(1H, d),7.21(1H, m), 6.78(1H, d), 3.70(2H, m), 2.23(2H, q), 1.27(3H, t),1.14(3H, t)

EXAMPLE 3: Synthesis of N-isopropyl-N′-(1-phenyliminopropyl)thiourea

[0054] N-phenylpropionamide (7.46 g, 0.05 mol) and pyridine (13.8 g,0.18 mol) were dissolved in dichloromethane (300 g), and the mixture wascooled to 0° C. And then phosphorus oxychloride (8.43 g, 0.05 mol) wasadded dropwise thereto for 2 hours, and then the mixture was stirred atroom temperature (20° C.) for 2 hours to produceN-phenylpropionimidoylchloride.

[0055] Subsequently, the reactant was slowly added dropwise to thereaction vessel containing the mixture of potassium isothiocyanide (7.3g, 0.08 mol) and sodium carbonate (15.9 g, 0.15 mol) in acetone (50 ml)at the temperature of 10° C. or less for 2 hours, and then the mixturewas stirred for 1 hour to produce N-phenylpropionimidoyl isothiocyanate.And isopropylamine (5.9 g, 0.1 mol) was added dropwise theretomaintaining the temperature of 10° C. or less for 2 hours, and then themixture was stirred for 1 hour.

[0056] After the reaction was completed, the title compound (8.1 g, 0.03mol) was obtained in a yield of 65% according to the same procedure asExample 1.

[0057]¹H NMR (CDCl₃) δ 11.80(1H, s, br), 7.92(1H, s, br), 7.35(2H, m),7.13(1H, t), 6.79(2H, d), 4.50(1H, m), 2.25(2H, q), 1.28(3H, s),1.22(3H, s), 1.17 (3H, t)

EXAMPLE 4: Synthesis of 2-chloro-N-(α-cyano-2-thenyl)acetamide

[0058] Amino-thiophen-2-yl-acetonitrile hydrochloride(17.5 g, 0.1 mol)was dissolved in dichloromethane (100 ml), and then pyridine (16.6 g,0.21 mol) was dropwise thereto. The mixture was cooled to 10° C., andthen chloroacetyl chloride (12.4 g, 0.11 mol) was added dropwise theretofor 1 hour.

[0059] After the reaction was completed, the mixture was washed threetimes with each time water (60 ml), the solvent was removed bydistillation under reduced pressure, and the residue was recrystallizedfrom toluene to give the title compound (19.8 g, 0.09 mol) in a yield of92%.

[0060]¹H NMR (CDCl₃): δ 7.42(1H, d), 7.32(1H, d), 7.23(1H, s, br),7.05(1H, t), 6.28(1H, d), 4.15(2H, s)

EXAMPLE 5: Synthesis of 2-bromo-N-(α-cyano-2-thenyl)acetamide

[0061] Amino-thiophen-2-yl-acetonitrile hydrochloride (8.8 g, 0.05 mol)was dissolved in dichloromethane (50 ml), and then pyridine (8.7 g, 0.11mol) was dropwise thereto. The mixture was cooled to 0° C., and thenbromoacetyl bromide (10.1 g, 0.05 mol) was added dropwise thereto for 1hour.

[0062] After the reaction was completed, the title compound (11.4 g,0.04 mol) was obtained in a yield of 88% according to the same procedureas Example 4.

[0063]¹H NMR (CDCl₃): δ 7.41(1H, m), 7.32(1H, m), 7.11(1H, d, br),7.05(1H, m), 6.25(1H, d), 3.94(2H, s)

EXAMPLE 6: Synthesis ofN-(α-cyano-2-thenyl)-4-ethyl-2-(ethylamino)-5-thiazolecarboxamide

[0064] Method 1)

[0065] N-ethyl-N′-(1-phenyliminopropyl)thiourea (23.5 g, 0.1 mol) and2-chloro-N-(α-cyano-2-thenyl)acetamide (21.4 g, 0.1 mol) were dissolvedin methaniol (200 ml). And then triethylamine (15.2 g, 0.15 mol) wasintroduced therein, and the mixture was refluxed for 8 hours.

[0066] After the reaction was completed, the mixture was cooled andfiltered. The residue was washed with cool methanol, and dried to givethe title compound (24.0 g, 0.08 mol) in a yield of 75%.

[0067] Method 2)

[0068] N-(1-(2,6-dichlorophenyl)iminopropyl)-N′-ethylthiourea (3.1 g,0.1 mol) and 2-chloro-N-(α-cyano-2-thenyl)acetamide (21.4 g, 0.1 mol)were dissolved in methanol (200 mg). And then triethylamine (15.2 g,0.15 mol) was introduced therein, and the mixture was refluxed for 8hours.

[0069] After the reaction was completed, the mixture was cooled by usingcool methanol, and dried to give the title compound (24.0 g, 0.08 mol)in a yield of 75%.

[0070]¹H NMR (CDCl₃): δ 7.38(1H, d), 7.33(1H, d), 7.04(1H, t), 6.43(1H,d), 5.94(1H, d, br), 5.59(1H, s, br), 3.26(2H, q), 2.93(2H, q), 1.26(6H,m)

EXAMPLE 7: Synthesis ofN-(α-cyano-2-thenyl)-2-(ethylamino)-4-methyl-5-thiazolecarboxamide

[0071]N-ethyl-N′-(1-phenyliminopropyl)thiourea (22.1 g, 0.1 mol) and2-chloro-N-(α-cyano-2-thenyl)acetamide(21.4 g, 0.1 mol) were dissolvedin ethanol (200 mg). And then diisopropylethylamine (15.5 g, 0.12 mol)was introduced therein, and the mixture was stirred at the temperatureof 60° C. for 10 hours.

[0072] After the reaction was completed, the solvent was removed bydistillation under reduced pressure to produce a brown solid. The solidwas recrystallized from the mixture solution of toluene and water(v/v=10/1) to give the title compound (22.1 g, 0.07 mol) in a yield of72%.

[0073]¹H NMR (CDCl₃) δ 7.36(1H, d), 7.30(1H, d), 7.04(1H, t), 6.10(1H,d), 5.99(1H, s, br), 3.28(2H, q), 2.53(3H, s), 1.30(3H, t)

EXAMPLE 8: Synthesis ofN-(α-cyano-2-thenyl)-4-ethyl-2-(isopropylamino)-5-thiazolecarboxamide

[0074]N-isopropyl-N′-(1-phenyliminopropyl)thiourea (2.5 g, 0.01 mol) and2-bromo-N-(α-cyano-2-thenyl)acetamide (2.6 g, 0.01 mol) were dissolvedin methanol (20 ml). And then triethylamine (1.5 g, 0.02 mol) wasintroduced therein, and the mixture was stirred at the temperature of60° C. for 7 hours

[0075] After the reaction was completed, the solvent was removed bydistillation under reduced pressure to produce a brown solid. The solidwas recrystallized from the mixture solution of ethanol and water(v/v=1/1) to give the title compound (2.0 g, 0.01 mol) in a yield of60%.

[0076]¹H NMR (CDCl₃): δ 7.38(1H, d), 7.30(1H, d), 7.01(1H, t), 6.44(1H,d), 6.00(1H, d), 5.49(1H, s, br), 3.61(1H, m), 2.91(2H, q), 1.27(9H, m)

[0077] As described above, a 2-aminothiazolecarboxamide derivative offormula (I) can be prepared by using the intermediates of formulae (II)and (III) in the high yield, according to the process of the presentinvention. And the present process is more economic than theconventional process because of the high yield from the industrialviewpoint.

What is claimed is:
 1. A process for preparing a compound represented bythe following formula (I).

wherein R¹ represents straight-chain or branched C₁₋₅ alkyl, C₁₋₅haloalkyl, or C₃₋₆ cycloalkyl, and R² represents C₁₋₃ alkyl or C₁₋₃haloalkyl, characterized in that a compound represented by the followingformula (II):

wherein R¹ and R² are defined as previously described, and R³ representsphenyl which may be optionally mono- to penta-substituted independentlyby chloro, methoxy, ethoxy, phenoxy or nitro, is reacted with a compoundrepresented by the following formula (III):

wherein Y represents a leaving group, in a solvent and in the presenceof a base.
 2. The process according to claim 1, wherein Y representschloride or bromide.
 3. The process according to claim 1, wherein thesolvent is an alcohol selected from a group consisting of methanol,ethanol and isopropyl alcohol; an aromatic hydrocarbon selected from agroup consisting of benzene, toluene and xylene; an ether selected froma group consisting of diethylether, dioxane, 1,2-dimethoxyethane andtetrahydrofuran, a ketone selected from a group consisting of acetone,methylethyl ketone and cyclohexanone; a nitrile selected from a groupconsisting of acetonitrile and propionitrile, a halogenated hydrocarbonselected from a group consisting of dichloromethane, 1,2-dichloroethaneand chloroform, an ester selected from a group consisting of methylacetate and ethyl acetate; or a polar solvent selected from a groupconsisting of N,N-diethylformamide, N,N-dimethylacetamide and dimethylsulfoxide.
 4. The process according to claim 3, wherein the solvent isthe alcohol.
 5. The process according to claim 1, wherein the base is anorganic base selected from a group consisting, of triethylamine,tributylamine, diisopropylethylamine, N,N-dimethylaniline, pyridine and4-dimethylamino pyridine, or an inorganic base selected from a groupconsisting of sodium hydroxide, potassium hydroxide, potassiumcarbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, sodiumhydride and potassium hydride.
 6. The process according to claim 5,wherein the base is the organic base.
 7. The process according to claim1, wherein the reaction is carried out at the temperature between 20° C.and 120° C. for 8 to 12 hours.
 8. A compound represented by thefollowing formula (II)

wherein R¹, R² and R³ are defined as claim
 1. 9. The compound accordingto claim 8, wherein R¹ and R² independently of each other representethyl.
 10. A compound represented by the following formula (III)

wherein Y is defined as claim 1.